5gtj
CRYSTAL STRUCTURE OF CATALYTICALLY ACTIVE FORM OF HUMAN DUSP26
Structural highlights
FunctionDUS26_HUMAN Inactivates MAPK1 and MAPK3 which leads to dephosphorylation of heat shock factor protein 4 and a reduction in its DNA-binding activity. Inhibits MAP kinase p38 by dephosphorylating it and inhibits p38-mediated apoptosis in anaplastic thyroid cancer cells. Can also induce activation of MAP kinase p38 and c-Jun N-terminal kinase (JNK).[1] [2] [3] [4] Publication Abstract from PubMedHuman dual-specificity phosphatase 26 (DUSP26) is a novel target for anticancer therapy because its dephosphorylation of the p53 tumor suppressor regulates the apoptosis of cancer cells. DUSP26 inhibition results in neuroblastoma cell cytotoxicity through p53-mediated apoptosis. Despite the previous structural studies of DUSP26 catalytic domain (residues 61-211, DUSP26-C), the high-resolution structure of its catalytically active form has not been resolved. In this study, we determined the crystal structure of a catalytically active form of DUSP26 (residues 39-211, DUSP26-N) with an additional N-terminal region at 2.0 A resolution. Unlike the C-terminal domain-swapped dimeric structure of DUSP26-C, the DUSP26-N (C152S) monomer adopts a fold-back conformation of the C-terminal alpha8-helix and has an additional alpha1-helix in the N-terminal region. Consistent with the canonically active conformation of its protein tyrosine phosphate-binding loop (PTP loop) observed in the structure, the phosphatase assay results demonstrated that DUSP26-N has significantly higher catalytic activity than DUSP26-C. Furthermore, size exclusion chromatography-multiangle laser scattering (SEC-MALS) measurements showed that DUSP26-N (C152S) exists as a monomer in solution. Notably, the crystal structure of DUSP26-N (C152S) revealed that the N-terminal region of DUSP26-N (C152S) serves a scaffolding role by positioning the surrounding alpha7-alpha8 loop for interaction with the PTP-loop through formation of an extensive hydrogen bond network, which seems to be critical in making the PTP-loop conformation competent for phosphatase activity. Our study provides the first high-resolution structure of a catalytically active form of DUSP26, which will contribute to the structure-based rational design of novel DUSP26-targeting anticancer therapeutics. Structural Insight into the Critical Role of the N-Terminal Region in the Catalytic Activity of Dual-Specificity Phosphatase 26.,Won EY, Lee SO, Lee DH, Lee D, Bae KH, Lee SC, Kim SJ, Chi SW PLoS One. 2016 Sep 1;11(9):e0162115. doi: 10.1371/journal.pone.0162115., eCollection 2016. PMID:27583453[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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